Comparison of enrofloxacin and ceftiofur sodium for the treatment of relapse of undifferentiated fever/bovine respiratory disease in feedlot cattle

Abstract

This commercial field trial compared the efficacy of enrofloxacin and ceftiofur sodium in beef cattle at high risk of developing undifferentiated fever (UF), also known as bovine respiratory disease (BRD) that received tilmicosin at feedlot arrival, were diagnosed and initially treated for UF with tilmicosin, and subsequently required a second UF treatment (first relapse). Feedlot cattle (n = 463) were randomly assigned to 2 experimental groups: ENRO or CEF. Second UF relapse, 3rd UF relapse, overall case fatality and BRD case fatality rates were lower in the ENRO group than in the CEF group (P < 0.05). There were no differences in average daily gain (allocation to re-implant date), chronicity, histophilosis case fatality or miscellaneous case fatality rates between the groups (P ≥ 0.05). A per-animal economic advantage of Can$57.08 was calculated for the ENRO group versus the CEF group. In feedlot cattle in western Canada at high risk of developing UF, it was more cost effective to administer enrofloxacin than ceftiofur sodium for treatment of UF relapse.

Introduction

Undifferentiated fever (UF), known as “shipping fever” or bovine respiratory disease (BRD), continues to be one of the most common animal health concerns in commercial beef feedlots (1–3). Although beef feedlot operations have become more sophisticated in managing health problems, significant economic losses from UF continue to be related to morbidity and mortality rates, reduced performance, and metaphylactic and therapeutic regimen costs (2). Therefore, it is important to seek the most cost-effective strategies for UF prevention and treatment, based on high quality clinical trial data.

Host, environmental, and management factors including the level of exposure to infectious agents, the choice of antimicrobial (AM) administered, the ability of the host to mount an appropriate immune response, and strategies implemented within the production system to control UF, may all influence the ability of an animal to fight disease or respond to treatment. Delayed recognition and treatment of UF is one of the most important factors related to UF relapse in cattle (4,5). New infection, recrudescence of pre-existing infection, misdiagnosis, and severe and irreparable damage caused by previous disease may also influence poor treatment response (4). As a result, the implementation of strategies which prevent disease, aid in identification of clinically ill animals or promote successful treatment may help to mitigate significant economic losses due to UF in commercial feedlots.

Infectious agents isolated from cases of UF in feedlot cattle include bacteria such as Mannheimia haemolytica, Pasteurella multocida, Mycoplasma spp., and Histophilus somni, and viruses such as infectious bovine rhinotracheitis (IBR) virus, parainfluenza-3 (PI₃) virus, bovine viral diarrhea virus, and bovine respiratory syncytial virus (2,6). Current management practices often target infectious agents/processes through the administration of metaphylactic and therapeutic injectable AMs, vaccines, bacterins, toxoids, and/or AMs delivered in feed (4,7). The choice of AM for relapse treatment for UF may be influenced by factors such as cost, route of administration and pharmacologic properties (such as bacterial sensitivity, duration of therapy, distribution within the body) (8); with desirable AM characteristics for UF relapse treatment including low cost, less frequent administration, short withdrawal times and high efficacy (reduced morbidity and case fatality rates).

For feedlot managers and veterinarians to make appropriate animal health decisions related to UF relapse treatment, commercial field trials are required to evaluate the cost-effectiveness of different AM in commercial feedlot settings. The purpose of this study was to compare the efficacy of enrofloxacin and ceftiofur sodium in relapse cases in commercial feedlot cattle at high risk of developing UF in western Canada.

Materials and methods

Study facilities

The study was conducted at 4 large commercial feedlots in southern Alberta, Canada, with 1-time capacities of 20 000 to 35 000 animals. The design of these feedlots is representative of the standard feedlot design in western Canada. Animals are housed in open air, dirt-floor pens arranged side-by-side with central feed alleys and 20% porosity fencing. The pens are designed to accommodate approximately 200 to 300 animals per pen.

There are 2 hospitals and handling facilities in each feedlot. Each hospital has a hydraulic chute equipped with an individual animal scale, a chute-side computer for individual animal data collection [AVHR, Feedlot Health Management Services (FHMS), Okotoks, Alberta], and separating alleys to facilitate cattle return to designated pens. Open air hospital pens are located adjacent to each hospital.

Feeding program

Study animals were conditioned to a high concentrate diet (approximately 85% to 90% barley, 8% to 10% barley silage, and 2% to 5% supplement on a 100% dry matter basis) over a 30- to 40-day period, and remained on the high-concentrate diet for the remainder of the study. Rations were formulated to meet or exceed the National Research Council nutritional requirements for feedlot cattle, and animals were fed ad libitum over the course of the study. The diets were delivered to pens once or twice daily, and daily feed allowances for each pen were recorded in commercial or in-house feedlot administration programs. The supplement was manufactured in a pellet or granular form by commercial feed mills (Masterfeeds, Calgary, Alberta, or Super-Tech Feeds, Strathmore, Alberta). Water was offered ad libitum over the course of the study.

Study animals

The animals used in the study were auction market-derived, crossbred, male, beef cattle at high risk of developing UF; they were approximately 5 to 10 mo old and weighed between 174 and 406 kg.

Upon arrival at the feedlot, the animals were moved through a hydraulic chute for procedures collectively known as processing. All animals received a subcutaneous (SC) injection of tilmicosin (Micotil; Provel, Division of Eli Lilly Canada, Guelph, Ontario), 10 mg/kg body weight (BW) as part of the UF prevention/control strategy. Each animal received a unique identification ear tag and a progesterone/estradiol benzoate growth implant in the middle third of the ear (Synovex-S; Ayerst Veterinary Laboratories, Guelph, Ontario). The animals were administered an IBR/PI₃ vaccine (Bovi-Shield-IBR/PI₃; Pfizer Canada, London, Ontario), a multivalent clostridial and Histophilus somni bacterin-toxoid [Fermicon 7-Somnugen; Boehringer-Ingelheim (Canada), Burlington, Ontario] and a Mannheimia haemolytica bacterin-toxoid (One Shot; Pfizer Canada). At 3 of the sites each animal received topically applied ivermectin (Ivomec-Pour On; Merck AgVet, Kirkland, Québec), 1 mL/10 kg BW, while at the other site each animal received both topically applied fenthion (Spotton; Bayer HealthCare Animal Health, Toronto, Ontario), 12 mL/295 kg BW and orally administered oxfendazole (Synanthic; Ayerst Veterinary Laboratories), 2.5 mL/50 kg BW for parasite control. Intact male animals were castrated at this time.

At approximately 76 d on feed, all animals were weighed, received a second growth implant in the middle third of the ear (Revalor-S; Hoechst Roussel AgriVet Co., North Sommerville, New Jersey, USA), and an intramuscular (IM) injection of IBR/PI₃ vaccine (Bovi-Shield-IBR/PI₃; Pfizer Canada).

Each pen was visually inspected once or twice daily by experienced animal health personnel for evidence of sickness; these personnel were blinded to the experimental status of animals. Animals were deemed “sick” based on subjective criteria such as general appearance and attitude, gauntness, and reluctance to move. “Sick” animals were presented to the hospital facility where an initial diagnosis of UF was made if the animal’s rectal temperature was ≥ 40.5°C and abnormal clinical signs directly attributable to organ systems other than the respiratory tract were not observed. Animals diagnosed with UF (first treatment) received a SC injection of tilmicosin (10 mg/kg BW), and were returned to their designated feedlot pen. “Sick” animals that were diagnosed with other diseases were treated according to a standard treatment protocol provided by the primary investigator.

Experimental design

Animals diagnosed with UF for a second time (first relapse) were eligible for inclusion in the trial. A first UF relapse case was defined as an animal with 1 previous UF diagnosis no less than 72 h after the last UF treatment administration, a rectal temperature ≥ 40.0°C, and no abnormal clinical signs referable to organ systems other than the respiratory system. Animals diagnosed with UF first relapse were weighed and randomly assigned to 1 of 2 experimental groups (ENRO, n = 232 or CEF, n = 231). Animals in the ENRO group received a SC injection of enrofloxacin (Baytril-100; Bayer HealthCare Animal Health) in the neck at a dosage of 2.5 mg/kg BW once a day for 3 d. Animals in the CEF group received an IM injection of ceftiofur sodium (Excenel; The Upjohn Company, Animal Health Division, Orangeville, Ontario) in the neck at a dosage of 1.0 mg/kg BW once a day for 3 d. Animals in both experimental groups were housed in designated hospital pens for the 3-day treatment period and were then returned to their original feedlot pens.

Trial animals identified as “sick” by animal health personnel subsequent to the first UF relapse treatment regimen were presented to the hospital facility. A second UF relapse case was defined as an animal with 2 previous UF diagnoses, while a third UF relapse case was defined as an animal that had been previously treated for UF 3 times. Both of these definitions also required a rectal temperature ≥ 40.0°C, no abnormal clinical signs referable to organ systems other than the respiratory system, and no treatment within 24 h of the last UF treatment. Both 2nd and 3rd UF cases were treated with the AM regimen (once a day for 3 d) of their respective experimental group (ENRO or CEF) and returned to their original feedlot pen after therapy. Once an animal was treated as a 3rd UF relapse, no further treatment for UF was attempted. Cattle identified as “sick” after receiving treatment for a 3rd UF relapse were deemed to be “chronics.”

The animal health events of each animal were followed from allocation to slaughter. “Chronics” that did not die were classified as wastage. The cause of death for each animal that died during the study was determined by a veterinarian based on clinical history and gross postmortem examination findings. If the cause of death could not be determined by a gross postmortem examination, representative tissue samples were submitted to the Regional Veterinary Diagnostic Laboratory in Airdrie, Alberta, to investigate the cause of death.

Data collection and statistical analysis

All animals were individually weighed at allocation, during re-implant administration, and at the time of each UF treatment. Weighing conditions were the same for animals in each treatment group at each weight measurement time point, and all measurements and treatment events including treatment date, presumptive diagnosis, drug(s) used, and dose(s) administered were recorded in the chute-side computer system (AVHR). Definitions used for calculation of animal health and feedlot performance variables are summarized in Table 1.

Table 1.

Definitions of animals health and feedlot performance for the comparison of enrofloxacin and ceftiofur sodium for the treatment of relapse cases of undifferentiated fever/bovine respiratory disease in feedlot cattle

	Definitiona
Animal health variable
Second UF relapse rateb	= number of 2nd UF relapses/number of 1st UF relapses
Third UF relapse ratec	= number of 3rd UF relapses/number of 2nd UF relapses
Chronicity	= number of animals treated > 4 times for UF/number of 1st UF relapses
Wastage	= number of animals treated > 4 times for UF that did not die/number of 1st UF relapses
Overall case fatality rate	= number of mortalities due to all causes/number of 1st UF relapses
BRD case fatality rate	= number of mortalities due to BRD/number of 1st UF relapses
Histophilosis case fatality rate	= number of mortalities due to histophilosis/number of 1st UF relapses
Miscellaneous case fatality rate	= number of mortalities due to causes other than UF or histophilosis/ number of 1st UF relapses
Feedlot performance variable
Average daily gain (kg/d)	= (weight at re-implant minus weight at allocation)/number days from allocation to re-implant

^aUF — undifferentiated fever, BRD — bovine respiratory disease, histophilosis — gross postmortem findings consistent with Histophilus somni infection (22).

^bCase definition for 2nd relapse = 2 previous diagnoses of UF, fever ≥ 40.0°C with no abnormal clinical signs referable to organ systems other than the respiratory system, and no treatment within 24 h of the last UF treatment.

^cCase definition for 3rd relapse = 3 previous diagnoses of UF, fever ≥ 40.0°C with no abnormal clinical signs referable to organ systems other than the respiratory system, and no treatment within 24 h of the last UF treatment.

The individual animal was the experimental unit. The animal health variables were compared between the experimental groups using Poisson regression in a log linear model for experimental group effects after accounting for clustering of observation (feedlot nested within year) using generalized estimating equations (9).

Allocation weight, re-implant weight, and average daily gain (ADG) (allocation to re-implant) variables were compared between the experimental groups using least squares analysis of variance after accounting for clustering of observation (feedlot nested within year) as a random effect (10). Allocation weight was tested as a covariate of re-implant weight and ADG (allocation to re-implant), and included in the final models for these parameters if significant effects were present (P < 0.05). Animals were excluded from these analyses if they had incomplete weight/performance data, were less than 14 d from allocation to re-implant, or died over the course of the study.

Economic analysis

The relative cost-effectiveness of treating the 2 experimental groups was calculated using a computer spreadsheet program (Microsoft Office Excel 1997; Microsoft Corporation, Redmond, Washington, USA) that simulates all economic aspects of feedlot production (7,11,12). Outcome variables describing the animal health and feedlot performance (live weight basis ADG) of each experimental group were incorporated into the model when significant differences (P < 0.05) existed between the experimental groups. When there were no significant differences (P ≥ 0.05) between the experimental groups, the animal health and feedlot performance variables of the CEF group were used for both experimental groups in the comparison. The ENRO program cost used in the economic model was Can$23.09/animal and the CEF program cost used was Can$20.65/animal. All other factors were fixed in the economic simulations between the 2 experimental groups; including the interest rate (4.0% per annum), and the purchase price (Can$120/100 lb BW, $264.56/100 kg BW) based on a 627 lb (284.4 kg) animal. A summary of the economic model input values and sensitivity analysis is presented in Table 2.

Table 2.

Economic model input values and sensitivity analysis in a comparison of enrofloxacin and ceftiofur sodium for the treatment of relapse cases of undifferentiated fever/bovine respiratory disease in feedlot cattle

Description	Unit	Input value	Change evaluated insensitivity analysis	Economic impacta,b ENRO versus CEF
Purchase price	$/100 lb body weight	$120.00	$10.00	$4.71
Interest rate	%/year	4.0%	1.0%	$0.19

^aAnimals in the ENRO group (n = 232) received enrofloxacin at 2.5 mg/kg BW via subcutaneous injection in the neck once a day for 3 d starting at the time of first UF relapse diagnosis. Animals in the CEF group (n = 231) received ceftiofur sodium at a rate of 10 mg/kg BW via intramuscular injection in the neck once a day for 3 d starting at the time of first UF relapse diagnosis.

^bAll economic impact values are expressed in Can$/animal and should be interpreted as the effect on the economic analysis that is associated with the input value changes evaluated in the sensitivity analysis.

Results

Animal health data including case morbidity and fatality rates are presented in Table 3. The 2nd UF relapse rate and 3rd UF relapse rate were significantly lower in the ENRO group than in the CEF group. The overall case fatality rate and the BRD case fatality rate were significantly lower in the ENRO group compared with the CEF group. Chronicity, wastage, histophilosis case fatality and miscellaneous case fatality rates were similar (P ≥ 0.05) between the 2 groups.

Table 3.

Animal health data summary in the comparison of enrofloxacin and ceftiofur sodium for the treatment of relapse cases of undifferentiated fever/bovine respiratory disease in feedlot cattle

Animal health variableb,c	Experimental groupa ENRO	CEF	RRd	95% CIe	P-value
Second UF relapse	30.17	40.26	0.75	0.59 to 0.95	0.018
Third UF relapse	31.43	46.24	0.68	0.57 to 0.81	< 0.001
Chronicity	13.79	18.18	0.76	0.57 to 1.02	0.066
Wastage	9.05	10.39	0.87	0.53 to 1.44	0.592
Overall case fatality	10.34	17.75	0.58	0.38 to 0.90	0.014
BRD case fatality	3.88	9.96	0.39	0.28 to 0.54	< 0.001
Histophilosis case fatality	6.03	6.49	0.93	0.53 to 1.63	0.798
Miscellaneous case fatality	0.43	1.30	0.33	0.03 to 3.80	0.376

^aAnimals in the ENRO group (n = 232) received enrofloxacin at 2.5 mg/kg BW via subcutaneous injection in the neck once a day for 3 d starting at the time of first UF relapse diagnosis. Animals in the CEF group (n = 231) received ceftiofur sodium at 10 mg/kg BW via intramuscular injection in the neck once a day for 3 d starting at the time of first UF relapse diagnosis.

^bUF — undifferentiated fever, BRD — bovine respiratory disease, histophilosis — lesions consistent with Histophilus somni infection.

^cSee Table 1 for definitions of variables.

^dRR (relative risk) — the ratio of the rate of disease in the ENRO group divided by the rate of the disease in the CEF group.

^e95% CI — the 95% confidence interval calculated for each RR.

The baseline and feedlot performance data are summarized in Table 4. There were no significant (P ≥ 0.05) differences in allocation weight, re-implant weight, or ADG from allocation to re-implant between the ENRO and CEF groups.

Table 4.

Baseline and feedlot performance data in the comparison of enrofloxacin and ceftiofur sodium for the treatment of relapse cases of undifferentiated fever/ bovine respiratory disease in feedlot cattle

	Experimental groupa,b
Variable	ENROc (n = 198)	CEFd (n = 169)	SE	P-value
Allocation weight (kg)	281.7	278.5	± 5.4	0.434
Re-implant weight (kg)e	382.6	379.6	± 13.8	0.452
Average daily gain (kg/d)	1.42	1.38	± 0.08	0.364
Days on feed	76.0	77.2	± 3.1	0.458

^aAnimals in the ENRO group received enrofloxacin at a rate of 2.5 mg/kg BW via subcutaneous injection in the neck once a day for 3 d starting at the time of first UF relapse diagnosis. Animals in the CEF group received ceftiofur sodium at a rate of 10 mg/kg BW via intramuscular injection in the neck once a day for 3 d starting at the time of first UF relapse diagnosis.

^bExperimental group numbers are least square means.

^cENRO: Animals were excluded from analysis if they had incomplete weight/performance data (n = 9), were < 14 d from allocation to re-implant (n = 1), or died over the course of the study (n = 24).

^dCEF: Animals were excluded from analysis if they had incomplete weight/performance data (n = 19), were < 14 d from allocation to re-implant (n = 2), or died over the course of the study (n = 41). SE — standard error, ADG — average daily gain from allocation to re-implant (see Table 1 for definition of ADG).

^eRe-implant weight has been adjusted for the significant (P < 0.050) effects of allocation weight.

The cost of using enrofloxacin was $3.92/allocated animal higher than in the CEF group ($2.47/allocated animal more for treatment at allocation and $1.45/allocated animal more for treatment at 2nd and/or 3rd relapse). Despite these higher treatment costs, there was a net economic advantage of Can$57.08/ animal in the ENRO group (see Table 5 for a breakdown of this number). In the sensitivity analysis, every $10/100 lb BW increase in purchase price resulted in an increase in the economic advantage in the ENRO group of $4.71/allocated animal and every $10/100 lb BW decrease in purchase price resulted in a decrease in the economic advantage in the ENRO group of $4.71/allocated animal compared to the CEF group (Table 2).

Table 5.

Economic analysis summary in the comparison of enrofloxacin and ceftiofur sodium for the treatment of relapse cases of undifferentiated fever/bovine respiratory disease in feedlot cattle

Outcome variableb	Economic impact per treated animala ENRO versus CEF
Second UF relapse rate	$3.45
Third UF relapse rate	$1.05
Overall case fatality rate	$56.50
Higher cost of enrofloxacin	−$3.92
Total economic advantage for ENRO	Can$57.08

^aAnimals in the ENRO group (n = 232) received enrofloxacin at a rate of 2.5 mg/kg BW via subcutaneous injection in the neck once a day for 3 d starting at the time of first UF relapse diagnosis. Animals in the CEF group (n = 231) received ceftiofur sodium at a rate of 10 mg/kg BW via intramuscular injection in the neck once a day for 3 d starting at the time of first UF relapse diagnosis.

^bSee Table 1 for definitions of variables.

Discussion

The results of this study indicate that it was more cost-effective to use enrofloxacin compared to ceftiofur sodium for the treatment of UF relapse cases in feedlot cattle at high risk of developing UF in western Canada. Cattle that received enrofloxacin for first UF relapse had fewer 2nd and 3rd UF relapses, as well as decreased overall and BRD case fatality rates compared to cattle that received ceftiofur sodium.

Specific reasons for the morbidity and case fatality differences between these 2 treatments are not known, although differences in the microbial sensitivity or other pharmacological characteristics of the 2 AM may have contributed to this finding. Enrofloxacin, a bactericidal AM in the fluoroquinolone family, is currently licensed in Canada for relapse treatment of UF. It is highly lipid-soluble and well-absorbed after IM or SC administration, and has in vivo activity against M. haemolytica, H. somni, and P. multocida and in vitro activity against Mycoplasma spp., all of which are important UF pathogens in cattle (13,14). Ceftiofur sodium, a bactericidal 3rd-generation cephalosporin, is effective against many gram-positive and gram-negative bacteria including M. haemolytica, P. multocida, and H. somni (15). Because ceftiofur sodium is highly protein-bound, it has an extended elimination half-life but poor ability to cross physiological barriers or to kill bacteria within cells (Mycoplasma spp., for example).

The role of M. bovis infection in acute, chronic, and unresponsive respiratory disease continues to be investigated (6,16,17). Haines et al (16) examined tissue specimens from cases of unresponsive UF/BRD in feedlot cattle that had been treated using an AM protocol of tilmicosin, trimethoprim and sulfadoxine, ceftiofur sodium, and sulbactam and ampicillin, and suggested that a lack of AM activity against M. bovis may have contributed to the poor response to treatment in those cases. However, sensitivity of M. bovis to enrofloxacin has been demonstrated in in vitro studies only, and further research on the effectiveness of enrofloxacin in unresponsive cases of UF/BRD related to M. bovis infection would be required to fully assess its specific activity against this pathogen.

This study was conducted from 1994 to 1996 as a part of the licensing requirements for enrofloxacin (Baytril-100; Bayer HealthCare Animal Health) in Canada. A large number of AMs have been investigated for initial treatment of UF in beef cattle (8); however, few studies have specifically investigated AM choices for non-responsive cases. Randomized clinical trials such as this are recommended for collecting high quality data to aid in therapeutic protocol development (8). The purpose of this study was to compare the efficacy of enrofloxacin and ceftiofur sodium for the treatment of UF relapse in a commercial feedlot setting to provide data for developing such therapeutic regimens.

The AMs compared in this study for relapse therapy are still available and commonly used in feedlot production (8). As a result, this paper brings useful information to veterinarians and feedlot producers for AM options in the treatment of UF relapse. The enrofloxacin and ceftiofur sodium regimens used in this study were as per the manufacturers label at the time. Subsequently, it was found that 1 injection of enrofloxacin was therapeutically similar to the once-a-day for 3 d regimen (18). As a result, the current day regimen for enrofloxacin administration is considered equivalent to the regimen in this study. Both the label at the time of this study and current labeling for ceftiofur sodium recommend treatment once a day for 3 d (with an extra 2 d treatment if required) (14). In this study, the ceftiofur regimen was limited to 3 d to standardize animal handling to 3 consecutive days for each treatment regimen for each of the 2 groups. Future studies should build on these data by investigating AMs for UF relapse therapy as part of current day management protocols, as well as including feedlot performance and carcass characteristic outcomes as part of cost-benefit evaluations.

Tilmicosin is licenced as a metaphylactic AM and as an AM for initial UF treatment in cattle (19) and in this study was used for both. While current practices commonly switch AM classes (such as macrolides, quinolones, tetracyclines, 3rd-generation cephalosporins, amphenicols) between metaphylaxis and UF treatment, at the time this study was conducted there were fewer AMs available and labeled for use in feedlot cattle, and tilmicosin was the only licensed long-acting new generation AM. As a result, it was considered the best choice for both metaphylaxis and treatment (20,21).

The economic analysis from this commercial field trial found that there was a Can$57.08/treated animal advantage to using enrofloxacin compared to ceftiofur sodium for UF relapse treatment in fall-placed calves in western Canada. The addition of enrofloxacin to therapeutic protocols improved economic margins for feedlot producers and improved animal health (morbidity and case fatality rates) in cases of UF with poor response to initial treatment.